Disease Manifestations in a Spinal and Bulbar Muscular Atrophy Patient after Feminization for Gender Reassignment (P2.003)

OBJECTIVE: To characterize spinal and bulbar muscular atrophy (SBMA) disease features in a patient who has undergone long term spironolactone treatment for male-to-female gender reassignment. BACKGROUND: SBMA is a neuromuscular disease caused by repeat expansion in the androgen receptor (AR) gene. SBMA is characterized by atrophy, fasciculations, and weakness in the limb and bulbar muscles starting in early adulthood. Females are asymptomatic or mildly symptomatic. Full development of the disease is dependent on androgens. Here we report a transgender individual with 15 years of feminizing androgen reduction with spironolactone who is fully symptomatic. Induction of mutant AR toxicity by spironolactone may explain these findings. DESIGN/METHODS: We assessed a 40 year old transgender male-to-female SBMA patient in comparison to her 43 year old affected brother. The patient’s genetic testing confirmed SBMA. We used MCF7 and PC12 cell models to evaluate the ability of spironolactone to induce the pathophysiological features of SBMA. AR nuclear translocation, formation of nuclear inclusions, and activation of androgen response elements were quantified in cells with and without exposure to spironolactone or dihydrotestosterone. RESULTS: The patient was well feminized but had typical clinical manifestations of SBMA. Her Adult Myopathy Assessment Tool (AMAT) score was 36/45, and her Timed Up and Go was 7.3 seconds, consistent with male SBMA patients her age. The patient’s brother’s AMAT total score was 35/45, and his Time Up and Go was 7.0 seconds. In cultured cells with mutant AR, spironolactone exposure caused concentration-dependent AR nuclear translocation and inclusion body formation. CONCLUSIONS: This SBMA patient with a history of long term feminization by spironolactone has clinical manifestations very similar to her non-feminized brother. Cell culture studies showed that spironolactone induces nuclear localization and inclusion body formation by the mutant AR, and it thus could cause toxicity of the mutant protein. Study Supported by: Disclosure: Dr. Lanman has nothing to disclose. Dr. Bakar has nothing to disclose. Dr. Burke has nothing to disclose. Dr. Kokkinis has nothing to disclose. Dr. Schindler has nothing to disclose. Dr. Bott has nothing to disclose. Dr. Harmison has nothing to disclose. Dr. Fischbeck has nothing to disclose. Dr. Grunseich has nothing to disclose.